WO2007090493A1 - Indazol-heteroaryl-derivate - Google Patents

Indazol-heteroaryl-derivate Download PDF

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Publication number
WO2007090493A1
WO2007090493A1 PCT/EP2007/000171 EP2007000171W WO2007090493A1 WO 2007090493 A1 WO2007090493 A1 WO 2007090493A1 EP 2007000171 W EP2007000171 W EP 2007000171W WO 2007090493 A1 WO2007090493 A1 WO 2007090493A1
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Prior art keywords
compounds
use according
solvates
treatment
stereoisomers
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PCT/EP2007/000171
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German (de)
English (en)
French (fr)
Inventor
Markus Klein
Rolf Gericke
Werner Mederski
Norbert Beier
Florian Lang
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Merck Patent Gmbh
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Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to US12/278,307 priority Critical patent/US7884126B2/en
Priority to DE502007001399T priority patent/DE502007001399D1/de
Priority to CA2641347A priority patent/CA2641347C/en
Priority to AU2007214085A priority patent/AU2007214085B2/en
Priority to AT07700206T priority patent/ATE440837T1/de
Priority to EP07700206A priority patent/EP1981878B1/de
Priority to JP2008552705A priority patent/JP5178531B2/ja
Publication of WO2007090493A1 publication Critical patent/WO2007090493A1/de
Priority to IL193211A priority patent/IL193211A/he

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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds and to the use of compounds in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular the tyrosine kinases and / or serine / threonine kinases, also pharmaceutical compositions containing these compounds, and the use of the compounds to treat kinase-related diseases.
  • the present invention relates to compounds in which the inhibition
  • CHK1 and CHK2 - kinase as well as the cell volume-regulated human kinase h-sgk (human serum and glucocorticoid dependent kinase or SGK) plays a role, also pharmaceutical compositions containing these compounds, as well as the use of the compounds for the treatment of CHK1-, CHK2- and SGK-related diseases.
  • Cell cycle control points are regulatory pathways that control the order and timing of cell cycle transitions. They ensure that important events, such as DNA replication and chromosomal segregation, are completed with high reliability. The control of this
  • CHK1 Ser / Thr kinase checkpoint kinase 1
  • CHK2 Another essential checkpoint kinase that plays a critical role in p53-dependent apoptosis is CHK2. Inhibition of CHK2 can protect normal sensitive tissue against chemotherapeutic agents (B.B.S. Zhou et al., Progress in Cell Cycle Research, Vol. 5, 413-421, 2003).
  • the compounds of the invention can be shown to inhibit checkpoint kinase activity.
  • Checkpoint kinase inhibitors can be shown to allow cells to inappropriately advance to the metaphase of mitosis, resulting in apoptosis of affected cells, and therefore possess antiproliferative effects.
  • the compounds of the invention can be used for the treatment of neoplastic disease.
  • the compounds of the present invention and their salts can be used against neoplastic diseases such as carcinoma of the brain, breast, ovary, lung, colon, prostate, skin or other tissues as well as leukemias and lymphomas, tumors of the central and peripheral nervous system and others Tumor types, like
  • Compounds may also be used in combination with a wide variety of DNA damaging agents, but may also be used as a single substance.
  • the present invention therefore relates to the use of the compounds according to the invention for the treatment of diseases or conditions in which an inhibition of the CHK1 and / or CHK2 activity is advantageous.
  • SGK belongs to the serine / threonine kinases.
  • the present invention further relates to the use of the compounds according to the invention, wherein the inhibition, regulation and / or modulation of the signal transduction of the cell volume-regulated human kinase h-sgk (human serum and glucocorticoid dependent kinase or SGK) plays a role in the treatment of SGK-related diseases.
  • human kinase h-sgk human serum and glucocorticoid dependent kinase or SGK
  • the SGK with the isoforms SGK-1, SGK-2 and SGK-3 are one
  • the compounds according to the invention are inhibitors of SGK-1. Further, they may be inhibitors of SGK-2 and / or SGK-3.
  • the present invention thus relates to the use of the compounds according to the invention which inhibit, regulate and / or modulate the signal transduction of SGK, compositions containing these compounds and methods for their use for the treatment of SGK-related diseases and conditions such as diabetes (eg diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary diseases and conditions such as diabetes (eg diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary diseases and conditions such as diabetes (eg diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary diseases and conditions such as diabetes (eg diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic
  • cardiovascular diseases e.g., cardiac fibrosis
  • the compounds according to the invention can also inhibit the growth of tumor cells and tumor metastases and are therefore suitable for tumor therapy.
  • the compounds according to the invention are furthermore used for the treatment of coagulopathies, such as, for example, dysfibrinogenemia, hypoproducinemia, hemophilia B 1 Stuart-Prower defect, prothrombin
  • the compounds of the invention may also be used therapeutically in the treatment of glaucoma or cataract.
  • the compounds of the invention are also used in the
  • the compounds of the invention may also be used therapeutically to increase learning and attention.
  • the compounds of the invention counteract cell aging and stress and thus increase life expectancy and fitness in old age.
  • the compounds according to the invention are also used in the treatment of tinitus.
  • the present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method of treatment said diseases comprising administering one or more of the compounds of the invention to a patient in need of such administration.
  • the host or patient may be of any mammalian species, e.g. A primate species, especially humans; Including rodents
  • mice Mice, rats and hamsters; Rabbits; Horses, cattle, dogs, 5
  • Animal models are of interest for experimental studies, providing a model for the treatment of human disease.
  • Compounds may also serve as reagents for testing kinase-dependent
  • HTR-FRET fluorescence polarization
  • FP fluorescence polarization
  • Phospho-AK phospho-antibodies
  • the phospho-AK binds only the phosphorylated substrate. This binding is detectable by chemiluminescence with a second peroxidase-conjugated anti-sheep antibody 5 (Ross et al., Biochem. J., 2002, 366, 977-981).
  • indazole derivatives are described as protein kinase inhibitors in WO 03/064397.
  • indazole derivatives are as kinase inhibitors in WO 2003097610 5. , , described.
  • indazole derivatives are disclosed as GSK-3 inhibitors in WO2003051847.
  • the invention relates to compounds selected from the group
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.
  • Salts of the compounds of the invention as well as so-called prodrug compounds are salts of the compounds of the invention as well as so-called prodrug compounds.
  • the term "effective amount” means the amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.
  • terapéuticaally effective amount means an amount that, compared to a corresponding subject, this
  • Quantity has not received has the following: improved curative treatment, cure, prevention or elimination of a disease, a clinical picture, a disease state, a condition, a disorder or side effects or even a reduction in the progression of a disease, a condition or a disorder.
  • terapéuticaally effective amount also includes the amounts effective to increase normal physiological function.
  • the invention also provides the use of mixtures of the compounds of formula I, e.g. Mixtures of two diastereomers, e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000.
  • a c These are particularly preferably mixtures of stereoisomeric compounds.
  • the starting materials can, if desired, also be formed in situ, O0 so that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of formula I.
  • the compounds according to the invention can preferably be obtained by reacting compounds of the formula II
  • L preferably denotes F, Cl, Br, I or a freely modified or reactively modified OH group, for example an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or Arylsulfonyloxy having 6-10 C atoms (preferably phenyl or p-Tolylsulfonyl- oxy).
  • L is preferably F.
  • the reaction is usually carried out in an inert solvent.
  • the reaction time is between a few minutes and 14 days, depending on the conditions used, the reaction temperature between about 0 ° and 150 °, usually between 15 ° and 120 °, more preferably between 50 and 100 0 C.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol),
  • Ethylene glycol dimethyl ether diglyme
  • Ketones such as acetone or butanone
  • Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile
  • Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide
  • Carboxylic acids such as formic acid or acetic acid
  • Nitro compounds such as nitromethane or nitrobenzene
  • Esters such as ethyl acetate or
  • A is alkyl having 1, 2, 3, 4, 5 or 6 C atoms
  • R is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, furyl, thienyl, pyridyl, o-, m- or p-methoxyphenyl, o-, m- or p -Chlorophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-bromophenyl, o-, m- or p-fluorophenyl, o-, m- or p-methylphenyl, o-, m- or p -Ethylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p- (2-dimethylamino-e
  • L is preferably F, Cl 1 Br, I or a free or reactively modified OH group such as an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms
  • L is preferably Cl.
  • the reaction is usually carried out in an inert solvent.
  • Reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about 0 ° and 150 °, normally between 15 ° and 120 °, particularly preferably between 20 and 100 0 C. 5 Suitable solvents are those mentioned above, preferred is DMF.
  • the reaction is optionally carried out in the presence of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amine component of the formula IV may also be favorable.
  • the reaction time varies depending on the applied
  • reaction temperature between about 0 ° and 150 °, usually between 20 ° and
  • Suitable inert solvents are those mentioned above.
  • ester cleavage is carried out under standard conditions as the
  • the abovementioned compounds according to the invention can be used in their final non-salt form.
  • the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases according to procedures known in the art.
  • Pharmaceutically acceptable salt forms of the compounds of the invention are mostly prepared conventionally. If the compound according to the invention contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt.
  • Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide
  • Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide
  • Alkali metal alcoholates e.g. Potassium ethanolate and sodium propanolate
  • various organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, e.g.
  • Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and
  • Benzenesulfonate as well as other organic acids and their treating salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like.
  • pharmaceutically acceptable acid addition salts of the compounds according to the invention include the following: acetate,
  • Methyl benzoate monohydrogen phosphate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is none
  • the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium , Sodium and zinc salts, but this should not be limiting.
  • Preferred among the above salts are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium.
  • Salts of the compounds of this invention derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, e.g. Arginine, betaine, caffeine, chloroprocaine, choline,
  • Triethylamine trimethylamine, tripropylamine and tris (hydroxymethyl) - methylamine (tromethamine), but this is not intended to be limiting.
  • Compounds of the present invention containing basic nitrogen-containing groups can be prepared with agents such as (C 1 -C 4 ) alkyl halides, eg, methyl, ethyl, isopropyl, and tert-butyl chloride, bromide, and iodide; Di (C 1 -C 4 ) alkyl sulfates, eg dimethyl, diethyl and diamylsulfate; (C 10 -
  • alkyl halides such as decyl, dodecyl, lauryl, myristyl and
  • the above-mentioned pharmaceutical salts which are preferable include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, 25 meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate , Sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to be limiting.
  • the acid addition salts of basic compounds are prepared by bringing the free base form with a sufficient amount of the desired acid, causing the formation of the salt in a conventional manner.
  • the free base can be brought by contacting the
  • Salt form with a base and isolate the free base in the usual way
  • the pharmaceutically acceptable base addition salts of the compounds of the invention are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
  • metals are sodium, potassium, magnesium and calcium.
  • Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
  • the base addition salts of acidic compounds of the present invention ⁇ J C are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner.
  • the free acid can be obtained by contacting the salt form with an acid and isolating the free
  • salts differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.
  • a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts. To typical multiple salt forms
  • OQ include, for example, bitartrate, diacetate, difumarate, dimeglumine,
  • an active ingredient is to be understood that a compound of the invention in the form of one of its salts, in particular when that salt form imparts to the active ingredient improved pharmacokinetic properties as compared to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used.
  • the pharmaceutically acceptable salt form of the active ingredient can also be this
  • the active ingredient first conferred a desired pharmacokinetic property that it did not previously possess, and may even positively affect the pharmacodynamics of that agent in terms of its therapeutic efficacy in the body.
  • the invention further relates to medicaments containing at least one compound according to the invention and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
  • compositions may take the form of dosage units containing
  • Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound according to the invention, depending on the treatment
  • 30 unit formulations are those containing a daily dose or sub-dose, as indicated above, or a corresponding fraction thereof of an active ingredient.
  • pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
  • Pharmaceutical formulations may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) Ways, adapt.
  • Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the drug together with the carrier (s) or excipient (s).
  • An oral administration adapted pharmaceutical formulations - j 5 can be used as separate units, such as capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. 20
  • the active ingredient component in the form of a tablet or capsule, can be mixed with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as
  • O0 starch or mannitol is mixed.
  • a flavor, preservative, dispersant and dye may also be present.
  • Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
  • Lubricants such as e.g. fumed silica, talc,
  • Magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
  • a disintegrants or solubilizers such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
  • suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture.
  • suitable binders include starch, gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
  • the lubricating agents used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing, adding a lubricant and a disintegrating agent and pressing the whole into tablets.
  • a powder mixture is prepared by dissolving the appropriately comminuted compound with a diluent or a base as described above, and optionally with a binder, e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution reducer, such as e.g.
  • Paraffin Paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, e.g. Bentonite, kaolin or dicalcium phosphate is mixed.
  • the powder mixture can be granulated by mixing it with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve.
  • a binder e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve.
  • Granulation can be run through the powder mixture through a tabletting machine, resulting in irregularly shaped lumps in
  • Granules are broken up.
  • the granules can be added by adding of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds.
  • the greased mixture is then compressed into tablets.
  • the compounds according to the invention can also be combined with a free-flowing inert carrier and then pressed directly into tablets without carrying out the granulation or dry-pressing steps.
  • a transparent or opaque protective layer consisting of a shellac sealant, a layer of sugar or polymeric material and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.
  • Oral fluids such as solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound.
  • Syrups can be made by dissolving the compound in an appropriate taste aqueous solution while using elixirs
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives, e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can also be added.
  • the dosage unit formulations for oral administration may optionally be encapsulated in microcapsules.
  • the formulation can also be prepared so that the release is prolonged or retarded, such as by coating or embedding particulate material in polymers, wax, etc. 35
  • the compounds according to the invention as well as salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds can also be coupled with soluble polymers as targeted drug carriers.
  • soluble polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
  • Biodegradable polymers suitable for the controlled release of a drug e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyano-acrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches for prolonged, intimate contact with the epidermis of the recipient.
  • the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be used with either a paraffinic or a water-miscible cream base. Alternatively, the active ingredient can become a
  • Cream can be formulated with an oil-in-water cream base or a water-in-oil base.
  • the pharmaceutical formulations adapted for topical application to the eye include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
  • Formulations include lozenges, lozenges and mouthwashes.
  • compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
  • Adapted for nasal administration of pharmaceutical formulations in which the carrier substance is a solid comprise a coarse powder having a particle size O Q, for example in the range 20-500
  • Microns administered in the manner in which snuff is received i. by rapid inhalation via the nasal passages from a container held close to the nose with the powder.
  • compositions adapted for administration by inhalation include fine particulate dusts or nebulas containing various types of pressurized dosing dispensers
  • Aerosols, nebulizers or insufflators can be generated.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
  • the formulations may be administered in single or multiple dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use.
  • Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
  • formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
  • a therapeutically effective amount of a compound of the invention will depend on a number of factors including, for example, age and age Weight of the animal, the exact disease state that requires treatment, and its severity, the nature of the formulation and the route of administration, and is ultimately determined by the attending physician or veterinarian.
  • an effective amount of a compound of the invention for the treatment of neoplastic growth, eg, colon or breast carcinoma is generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg body weight per day.
  • the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same.
  • An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
  • the invention furthermore relates to medicaments comprising at least one compound according to the invention and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further active pharmaceutical ingredient.
  • the invention also relates to a kit consisting of separate packings of (a) an effective amount of a compound of the invention and / or its pharmaceutically usable derivatives, solvates and
  • the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
  • suitable containers such as boxes or boxes, individual bottles, bags or ampoules.
  • the set may e.g. separate
  • Ampoules contain, in each of which an effective amount of a compound of the invention and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug or dissolved in lyophilized form.
  • CHK1-mediated disorder includes any disorder, disease or condition caused or characterized by an increase in CHK1 expression or activity or which requires CHK1 activity.
  • CHK1-mediated disorder further includes any disorder, disease or condition in which inhibition of CHK1 activity is beneficial.
  • CHK1 inhibition can be used to achieve a beneficial therapeutic or prophylactic effect, for example in patients with a proliferative disorder.
  • proliferative disorders include chronic inflammatory proliferative disorders, eg, psoriasis and rheumatoid arthritis, proliferative eye disorders, eg, diabetic retinopathy, benign proliferative disorders, eg, hemangiomas, as well as cancer.
  • cancer refers to a cellular disorder caused by an uncontrolled or incorrect regulated cell proliferation, decreased cell differentiation, the inappropriate ability to invade surrounding tissue, and / or the ability to establish new growth at ectopic sites.
  • cancer includes, but is not limited to, solid tumors and blood-borne tumors.
  • cancer includes disorders of the skin, tissues, organs, bones, cartilage, blood and vessels.
  • cancer further includes primary and metastatic cancers.
  • Non-limiting examples of solid tumors that can be treated with the disclosed CHK1 inhibitors include i.a. Pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, including metastatic breast cancer, prostate cancer, including androgen-dependent and androgen-independent prostate cancer, kidney cancer, including e.g. metastatic renal cell carcinoma, hepatocellular carcinoma, lung cancer, including e.g. non-small cell lung cancer (NSCLC),
  • NSCLC non-small cell lung cancer
  • BAC Bronchioloalveolar carcinoma
  • adenocarcinoma of the lung
  • Ovarian cancer including e.g. progressive epithelial or primary
  • Peritoneal, cervical, gastric, esophageal, head and neck including e.g. Head and neck squamous cell carcinoma, melanoma, neuroendocrine cancer, including metastatic neuroendocrine tumors, brain tumors, including e.g. Glioma, anaplastic oligodendroglioma, glioblastoma multiforme in adults and anaplastic astrocytoma in adults, bone cancer and soft tissue sarcoma.
  • Non-limiting examples of hematological malignancies that may be treated with the disclosed CHK1 inhibitors include: acute myeloid leukemia (AML), chronic myeologenic leukemia
  • CML CML blast phase
  • BP acute lymphoblastic leukemia
  • ALL chronic lymphocytic
  • CLL Leukemia
  • HD Hodgkin's Disease
  • NHL Non-Hodgkin's Lymphoma
  • MM multiple myeloma
  • MDS myelodysplastic syndromes
  • RARS blast excess refractory anemia
  • RAEB blast excess refractory anemia
  • the disclosed compounds of the invention are particularly useful in the treatment of cancers or cell types in which CHK1 protein or activity is upregulated, including, without limitation, rapidly proliferating cells and drug-resistant cells (Shyjan et al., U.S. Patent No. 6,723,498 (2004 ) as well as retinoblastomas, such as Rb-negative or inactivated cells (Gottifredi et al., Mol. Cell Biol., 21: 1066 (2001)), or in which the ARF p14 / p19 locus is inactivated or misregulated.
  • the disclosed CHK1 inhibitors are also particularly useful in the treatment of cancers or cell types in which another
  • Control point pathway is mutated or abolished, including, without limitation, cancers or cell types in which p53 or the p53 pathway is inactivated or abolished.
  • anticancer agent refers to any agent that is administered to a patient with cancer for the purpose of treating the cancer.
  • the anticancer treatment as defined herein may be used as a sole therapy or may include conventional surgery or radiation therapy or chemotherapy in addition to the compound of the present invention.
  • Such chemotherapy may include one or more of the following categories of anti-tumor agents: (i) antiproliferative / antineoplastic / DNA damaging agents and combinations thereof as used in medical oncology, such as alkylating agents (for example cisplatin, carboplatin, cyclophosphamide,
  • Antimetabolites e.g., antifolates, such as fluoropyrimidines, such as
  • Antitumor antibiotics e.g., anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,
  • idarubicin for example, mitomycin C, dactinomycin and mithramycin
  • antimitotic agents for example, vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine, and taxoids such as taxol and taxotere
  • Topoisomerase inhibitors for example epipodophyllotoxins such as etoposide and
  • cytostatic agents such as anti-estrogens (e.g., tamoxifen,
  • LHRH antagonists or LHRH agonists for example, goserelin, leuprorelin and buserelin
  • progesterone for example, megestrol acetate
  • inhibitors for example anastrozole, letrozole, vorazole and exemestane
  • inhibitors of 5 ⁇ -reductase such as finasteride
  • agents that inhibit the invasion of cancer cells for example, metalloproteinase inhibitors such as marimastat and inhibitors of the
  • inhibitors of growth factor function include growth factor antibody, growth factor receptor antibody (for example, the anti-erbb2 antibody trastuzumab
  • farnesyltransferase inhibitors for example, epidermal growth factor family inhibitors (for example, EGFR family tyrosine kinase inhibitors, such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazoline).
  • epidermal growth factor family inhibitors for example, EGFR family tyrosine kinase inhibitors, such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazoline.
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor (for example, the vascular endothelial cell growth factor bevacizumab antibody [Avastin TM], compounds such as those disclosed in published international patent applications WO 97/22596, WO 97 No. 30035, WO 97/32856 and WO 98/13354) and compounds which act by other mechanisms (for example, linomide, integrin ⁇ v ⁇ 3 inhibitors and angiostatin);
  • vascular endothelial growth factor for example, the vascular endothelial cell growth factor bevacizumab antibody [Avastin TM]
  • compounds which act by other mechanisms for example, linomide, integrin ⁇ v ⁇ 3 inhibitors and angiostatin
  • vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those directed against the targets listed above, such as ISIS 2503, an anti-Ras
  • gene therapy approaches including, for example, approaches to replace altered genes, such as altered p53 or altered BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches, those that include cytosine deaminase, thymidine kinase or a bacterial nitroreductase Use enzyme as well as approaches to increase patient tolerance to chemotherapy or radiation therapy, such as multi-drug resistance gene therapy; and
  • immunotherapy approaches including, for example, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to reduction T cell anergy, batches using transfected immune cells such as cytokine-transfected dendritic cells, batches using cytokine-transfected tumor cell lines, and anti-idiotypic antibody approaches.
  • cytokines such as interleukin 2, interleukin 4 or granul
  • the medicaments of Table 1 below are combined with the compounds according to the invention.
  • Vinorelbine IDN 5109 (Bayer) Vindesin A 105972 (Abbott)
  • Rhizoxin (Fujisawa) LU 223651 (BASF)
  • Epothilone B Novartis
  • ZD 6126 AstraZeneca
  • Auristatin PE (Teikoku NeuroPharma)
  • Taxoprexin (Protarga) CA-4 (OXiGENE)
  • Thymidylate pemetrexed (EIi Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG) CoFactor TM (BioKeys)
  • TNF-alpha-virulizine (Lorus Revimid (Celgene)
  • CapCell TM CYP450-N-acetylcysteine
  • Antagonist kappaB inhibitor, Encore
  • Efaproxiral oxygenator, receptor agonist, Leo
  • PI-88 heparanase antagonist
  • histamine H2 osteoclast inhibitor
  • SRL-172 T-cell doranidazole (apoptosis
  • PT-100 growth factor (differentiator, NIH)
  • Point MX6 apoptosis promoter
  • CDA-II apoptosis-Ro-31-7453 (apoptosis
  • SDX-101 apoptosis-brostallicin (apoptosis)
  • Mitoxantrone diflomotecan (Beaufourrinotecan (CPT-11) Ipsen)
  • Rhizoxin (Fujisawa) LU 223651 (BASF)
  • Epothilone B Novartis
  • ZD 6126 AstraZeneca
  • Auristatin PE (Teikoku NeuroPharma)
  • Taxoprexin (Protarga) CA-4 (OXiGENE)
  • TNF-alpha-virulizine (Lorus Revimid (Celgene)
  • RNA cyclic stimulant, Alfacell
  • AMP AMP agonist
  • ribapharm galarubicin
  • CapCell TM CYP450-R flurbiprofen (NF-1)
  • GCS-IOO gal3 inhibitor, Active Biotech
  • SR-31747 (IL-1 PG2 (hematopoietic)
  • SRL-172 T-cell (differentiator, NIH)
  • TLK-286 (glutathione-S-MAXIA)
  • PLC-brostallicin apoptosis
  • Such joint treatment can be achieved by simultaneously, sequentially or separately dosing the individual components of the treatment.
  • Such combination products employ the compounds of the invention.
  • the present compounds according to the invention are furthermore suitable as pharmaceutical active ingredients for mammals, in particular for humans, in the treatment of SGK-related diseases.
  • the invention thus relates to the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of Signal transduction of kinases plays a role.
  • Preferred is the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases which are affected by inhibition of SGK by the compounds of claim 1 ,
  • the present invention encompasses the use of the compounds of invention 10 according to claim 1 and / or physiologically acceptable salts and solvates thereof for the manufacture of a medicament for the treatment or prevention of diabetes (such as diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy ⁇ c pathophysiology and microangiopathy), obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertension, cardiovascular diseases (eg cardiac fibrosis after myocardial infarction, cardiac hypertrophy and heart failure, arteriosclerosis) and kidney diseases (eg glomerulosclerosis, nephrosclerosis, nephritis,
  • diabetes such as diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy ⁇ c pathophysiology and microangiopathy
  • obesity metabolic syndrome (dyslipidemia), systemic and pulmonary hypertension
  • cardiovascular diseases eg cardiac fibrosis after myocardial infarction, cardiac hypertrophy
  • fibrosis and inflammatory processes e.g., cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis,
  • the compounds according to the invention can also inhibit the growth of cancer, tumor cells and tumor metastases and are therefore suitable for tumor therapy.
  • the compounds of the invention are furthermore used for the treatment of coagulopathies, such as dysfibrinogenemia, Hypopro- konvertinämie, hemophilia B, Stuart Prower defect, prothrombin complex deficiency, coagulation, fibrinolysis, immuno coagulopathy or complex coagulopathies, and also with neuronal coagulopathies, such as dysfibrinogenemia, Hypopro- konvertinämie, hemophilia B, Stuart Prower defect, prothrombin complex deficiency, coagulation, fibrinolysis, immuno coagulopathy or complex coagulopathies, and also with neuronal coagulopathies, such as dysfibrinogenemia, Hypopro- konvertinämie, hemophilia B, Stuart Prower defect, prothrombin complex deficiency, coagulation, fibrinolysis, immuno coagulopathy or complex coagulopathies, and also with neuronal coagulopathies, such as dysfibrinogenemia, Hypopro- konvertinämie, hemophilia
  • Excitability eg epilepsy.
  • the compounds of the invention can also be used therapeutically in the treatment of glaucoma or cataract.
  • the compounds of the invention are also used in the
  • the compounds of the invention may also be used therapeutically to increase learning and attention.
  • Diabetes is preferably diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.
  • Cardiovascular diseases are preferably cardiac fibrosis after myocardial infarction, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis.
  • Kidney disease is preferably glomerulo-sclerosis, nephrosclerosis, nephritis, nephropathy, and electrolyte clearance disorder.
  • Fibrosis and inflammatory processes are preferably liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermitis, cystic fibrosis, scarring, Alzheimer's disease.
  • the compounds of the invention described in the Examples can be tested for kinase inhibitory activity in the assays described below.
  • Other assays are known in the literature and can be readily performed by those skilled in the art (see, eg, Dhanabal et al., Cancer Res. 59: 189-197; Xin et al., J. Biol. Chem. 274: 9116-9121; Sheu et Biol. 38: 237-248; Gimbrone et al., J. Natl. Cancer Inst. 52: 413-427; Nicosia et al., In Vitro 18: 538-549).
  • CHK1 kinase is expressed as a fusion protein with glutathione S-transferase in a baculovirus expression vector for the purpose of protein production in insect cells (Sf21, S. frugiperda) and subsequent affinity chromatographic purification.
  • insect cells Sf21, S. frugiperda
  • affinity chromatographic purification The culture, infection and disruption of the cells, as well as the column chromatographic purification of the fusion protein are carried out according to manufacturer-oriented generic work instructions.
  • Phospho-AK Phospho-antibodies
  • the phospho-antibody binds only the phosphorylated substrate. This binding is detectable by chemiluminescence with a second peroxidase-conjugated antibody (Ross et al., 2002, Biochem. J.).
  • test plates are 384-well streptavidin-coated flashplates
  • n 30 minutes before the test ul with 75 of assay buffer per well equilibrated.
  • the buffer is aspirated before starting the experiment and the components of the kinase reaction described below are pipetted onto the plate.
  • the CHK1 kinase, a biotinylated substrate peptide eg CHKtide:
  • KKKVSRSGLYRSPSMPENLNRPR is incubated with radiolabeled ATP in the presence and absence of test substances at 30 ° Celsius and a total volume of 50 ⁇ l. The reaction is stopped with 25 ⁇ l of a 0.2 M EDTA solution. After incubation for 30 min at room temperature.
  • bovine serum albumin (final concentration 0.1%) takes place shortly before use.
  • CHKtide solution biotinylated peptide substrate (Biotrend) stored as stock solution (concentration 0.15 mg / ml).
  • reaction buffer 8 mM MOPS pH7, 0.2 mM EDTA, 10 mM
  • the inhibition of SGK1 protein kinase can be achieved in the filter binding procedure
  • “usual work-up” means: add water if necessary, and, if necessary, adjust to pH values between 2 and 10, depending on the constitution of the final product, extracted with Ethyl acetate or dichloromethane, separates, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Eluent: ethyl acetate / methanol 9: 1. Mass spectrometry (MS): El (electron impact ionization) M +
  • APCI-MS atmospheric pressure chemical ionization - mass spectrometry (M + H) + .
  • Hewlett Packard HP 1100 series system with the following features: Ion source: electrospray (positive mode); Scan: 100-1000 m / z; Fragmentation voltage: 60 V; Gas temperature: 300 ° C, DAD: 220 nm. Flow rate: 2.4 ml / min. The splitter used after DAD reduces the flow rate for the MS to 0.75 ml / min.
  • Solvent LiChrosolv grade from Merck KGaA Solvent A: H 2 O (0.01% TFA)
  • Tetrakis (triphenylphosphine) palladium (0), 300 ml of ethylene glycol dimethyl ether and 200 ml of water are degassed several times and rendered inert with nitrogen.
  • O5 receives 2.9 g of 5- (3-amino-1H-indazol-5-yl) -furan-2-carboxylic acid tert-butyl ester ("A2a") as a colorless solid (74%).
  • A2a 5- (3-cyano-4-fluoro-phenyl) -furan-2-carboxylic acid isopropyl ester gives the compound 5- (3-amino-1H-indazol-5-yl) -furan-2-carboxylic acid isopropyl ester ( "A7").
  • 2-carboxylic acid tert-butyl ester are dissolved in 1 ml of trifluoroacetic acid and 3 ml of dichloromethane and stirred for 24 hours at room temperature.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared according to the invention, 9.38 g of NaH 2 PO 4 • 2H 2 O, 28.48 g Na 2 HPO 4 • 12 H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water , Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation.
  • This solution can be used in the form of eye drops.
  • Example D Ointment 500 mg of an active ingredient according to the invention are mixed with 99.5 g of Vaseline under aseptic conditions.
  • a mixture of 1 kg of active ingredient according to the invention, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way into tablets, such that each tablet contains 10 mg of active ingredient.
  • Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
  • a solution of 1 kg of the active compound according to the invention in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and closed under sterile conditions. Each vial contains 10 mg of active ingredient.

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PCT/EP2007/000171 2006-02-06 2007-01-10 Indazol-heteroaryl-derivate WO2007090493A1 (de)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US12/278,307 US7884126B2 (en) 2006-02-06 2007-01-10 Indazole-heteroaryl derivatives
DE502007001399T DE502007001399D1 (de) 2006-02-06 2007-01-10 Indazol-heteroaryl-derivate
CA2641347A CA2641347C (en) 2006-02-06 2007-01-10 Indazole-heteroaryl derivatives
AU2007214085A AU2007214085B2 (en) 2006-02-06 2007-01-10 Indazole heteroaryl derivatives
AT07700206T ATE440837T1 (de) 2006-02-06 2007-01-10 Indazol-heteroaryl-derivate
EP07700206A EP1981878B1 (de) 2006-02-06 2007-01-10 Indazol-heteroaryl-derivate
JP2008552705A JP5178531B2 (ja) 2006-02-06 2007-01-10 インダゾール−ヘテロアリール誘導体
IL193211A IL193211A (he) 2006-02-06 2008-08-03 נגזרות של אינדזול–הטרואריל ותכשירי רוקחות המכילים אותן

Applications Claiming Priority (2)

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DE102006005180A DE102006005180A1 (de) 2006-02-06 2006-02-06 Indazol-heteroaryl-derivate
DE102006005180.7 2006-02-06

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EP (1) EP1981878B1 (he)
JP (1) JP5178531B2 (he)
AR (1) AR059294A1 (he)
AT (1) ATE440837T1 (he)
AU (1) AU2007214085B2 (he)
CA (1) CA2641347C (he)
DE (2) DE102006005180A1 (he)
ES (1) ES2330388T3 (he)
IL (1) IL193211A (he)
WO (1) WO2007090493A1 (he)

Cited By (8)

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WO2009089352A1 (en) 2008-01-08 2009-07-16 Array Biopharma Inc. Pyrrolopyridines as kinase inhibitors
JP2011522849A (ja) * 2008-06-09 2011-08-04 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト 置換４−（インダゾリル）−１，４−ジヒドロピリジン類およびそれらの使用方法
WO2012074754A1 (en) 2010-11-16 2012-06-07 Array Biopharma Inc. Combination of checkpoint kinase 1 inhibitors and wee 1 kinase inhibitors
US8372842B2 (en) 2008-01-09 2013-02-12 Array Biopharma Inc. Pyrazolopyridines as kinase inhibitors
US8481557B2 (en) 2009-04-11 2013-07-09 Array Biopharma Inc. Method of treatment using checkpoint kinase 1 inhibitors
EP2990407A1 (en) 2008-05-13 2016-03-02 Array Biopharma, Inc. Pyrrolopyridines as kinase inhibitors
EP3461480A1 (en) 2017-09-27 2019-04-03 Onxeo Combination of a dna damage response cell cycle checkpoint inhibitors and belinostat for treating cancer
WO2022015979A1 (en) * 2020-07-15 2022-01-20 Ifm Due, Inc. Compounds and compositions for treating conditions associated with sting activity

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DE102008029072A1 (de) * 2008-06-10 2009-12-17 Lang, Florian, Prof. Dr.med. Sgk3 als therapeutisches und diagnostisches Target für Alterserkrankungen
WO2013006230A2 (en) 2011-07-01 2013-01-10 Fox Chase Cancer Center Combined inhibition of the vitamin d receptor and dna replication in the treatment of cancer
US9889141B2 (en) 2014-10-14 2018-02-13 Institute For Cancer Research Combined inhibition of the vitamin D receptor and poly(ADP) ribose polymerase (PARP) in the treatment of cancer
TWI725041B (zh) * 2015-07-23 2021-04-21 美商美國禮來大藥廠 用於治療神經母細胞瘤及/或軟組織肉瘤之chk1/2抑制劑

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WO2004062662A1 (fr) * 2002-12-12 2004-07-29 Aventis Pharma S.A. Derives d'aminoindazoles et leur utilisation comme inhibiteurs de kinases
WO2005123688A2 (de) * 2004-06-15 2005-12-29 Merck Patent Gmbh 3-aminoindazole derivate und ihre verwendung zur behandlung sgk-bedingten krankheiten

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EP1319001A1 (en) * 2000-09-22 2003-06-18 Smithkline Beecham Plc Pyrazolopyridines and pyrazolopyridazines as antidiabetics
AU2003227741A1 (en) * 2002-05-17 2003-12-02 Pharmacia Italia S.P.A. Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them

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WO2003051847A1 (en) * 2001-12-19 2003-06-26 Smithkline Beecham P.L.C. (1-h-indazol-3-yl) -amide derivatives as gsk-3 inhibitors
WO2004062662A1 (fr) * 2002-12-12 2004-07-29 Aventis Pharma S.A. Derives d'aminoindazoles et leur utilisation comme inhibiteurs de kinases
WO2005123688A2 (de) * 2004-06-15 2005-12-29 Merck Patent Gmbh 3-aminoindazole derivate und ihre verwendung zur behandlung sgk-bedingten krankheiten

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009089352A1 (en) 2008-01-08 2009-07-16 Array Biopharma Inc. Pyrrolopyridines as kinase inhibitors
US8841304B2 (en) 2008-01-08 2014-09-23 Array Biopharma, Inc. Pyrrolopyridines as kinase inhibitors
US8372842B2 (en) 2008-01-09 2013-02-12 Array Biopharma Inc. Pyrazolopyridines as kinase inhibitors
EP2990407A1 (en) 2008-05-13 2016-03-02 Array Biopharma, Inc. Pyrrolopyridines as kinase inhibitors
JP2011522849A (ja) * 2008-06-09 2011-08-04 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト 置換４−（インダゾリル）−１，４−ジヒドロピリジン類およびそれらの使用方法
US8481557B2 (en) 2009-04-11 2013-07-09 Array Biopharma Inc. Method of treatment using checkpoint kinase 1 inhibitors
US9155726B2 (en) 2009-04-11 2015-10-13 Array Biopharma Inc. Method of treatment using checkpoint kinase 1 inhibitors
WO2012074754A1 (en) 2010-11-16 2012-06-07 Array Biopharma Inc. Combination of checkpoint kinase 1 inhibitors and wee 1 kinase inhibitors
US9370567B2 (en) 2010-11-16 2016-06-21 Array Biopharma Inc. Combination of checkpoint kinase 1 inhibitors and WEE 1 kinase inhibitors
US10434094B2 (en) 2010-11-16 2019-10-08 Array Biopharma Inc. Combination of checkpoint kinase 1 inhibitors and wee 1 kinase inhibitors
EP3461480A1 (en) 2017-09-27 2019-04-03 Onxeo Combination of a dna damage response cell cycle checkpoint inhibitors and belinostat for treating cancer
WO2022015979A1 (en) * 2020-07-15 2022-01-20 Ifm Due, Inc. Compounds and compositions for treating conditions associated with sting activity

Also Published As

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AU2007214085A1 (en) 2007-08-16
ATE440837T1 (de) 2009-09-15
EP1981878A1 (de) 2008-10-22
JP5178531B2 (ja) 2013-04-10
US20090076091A1 (en) 2009-03-19
CA2641347C (en) 2014-10-14
CA2641347A1 (en) 2007-08-16
US7884126B2 (en) 2011-02-08
DE502007001399D1 (de) 2009-10-08
AU2007214085B2 (en) 2011-12-22
EP1981878B1 (de) 2009-08-26
ES2330388T3 (es) 2009-12-09
IL193211A0 (en) 2009-02-11
AR059294A1 (es) 2008-03-26
IL193211A (he) 2013-07-31
DE102006005180A1 (de) 2007-08-09
JP2009525969A (ja) 2009-07-16

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